The World Health Organization (WHO) this week published two reports spotlighting gaps in adequate medicines and diagnostic tests for treating and detecting invasive fungal diseases, such as Candida auris, including a dearth of new drugs and drug candidates in advanced trials.
More than 6.5 million fungal infections occur annually and cause 3.8 million deaths, according to WHO data.
"Invasive fungal infections threaten the lives of the most vulnerable, but countries lack the treatments needed to save lives," said Yukiko Nakatani, PhD, WHO interim assistant director-general for antimicrobial resistance, in a WHO news release. "Not only is the pipeline of new antifungal drugs and diagnostics insufficient, there is a void in fungal testing in low- and middle-income countries, even in district hospitals."
Only 4 recently approved antifungals, 3 in phase 3 trials
The WHO report on antifungal drugs notes that, in the past 10 years, only four new antifungal drugs have been approved by regulatory agencies in the United States, European Union, or China.
All four approved drugs have demonstrated activity against at least one fungal critical priority pathogen (CPP) according to the WHO Fungal priority pathogens list (FPPL), published in October 2022. The four CPPs are Aspergillus fumigatus, Candida albicans, Candida auris, and Cryptococcus neoformans. Two of the newly approved drugs show activity against three CPPs, one shows activity against two CPPs, and one against one CPP.
Only one of the approved drugs, however, meets any of the criteria that the WHO says is an indicator of innovation.
Invasive fungal infections threaten the lives of the most vulnerable, but countries lack the treatments needed to save lives.
In addition, nine antifungal drug candidates are in clinical development to use against CPPs, three in phase 3 trials (the most advanced), two in phase 2, and four in phase 1. Seven show evidence of activity against at least one CPP: Two have activity against all four, one candidate against three CPPs, and one against two CPPs. The CPPs can cause up to an 88% mortality rate, the WHO says.
Of the nine antifungal drugs in clinical development, four meet at least one innovation criterion, and two meet all four innovation criteria. Among the candidate drugs, only three address a new molecular target, one of which is still not clearly identified.
Issues with current antifungal treatments include serious side effects, frequent drug-drug interactions, limited dosage forms, and a need for prolonged hospital stays. The report highlights the urgent need for safer antifungal medicines. Children are particularly underserved, the report notes, with few clinical trials exploring pediatric dosing.
"WHO recommends investing in global surveillance, expanding financial incentives for drug discovery and development, funding basic research to help identify new and unexploited targets on fungi for medicines, and investigating treatments that work by enhancing patients' immune responses," according to the release.
Gaps in diagnostics
The new diagnostics report shows that, while commercially available tests can detect fungal CPPs and other serious fungi, they rely on well-equipped laboratories and trained staff, which means that most people in low- and middle-income countries (LMICs) cannot access. All countries, but particularly LMICs, need faster, more accurate, less expensive, and easier testing for a broad range of priority pathogens, including diagnostic tools at the point-of-care.
The report says that another gap is limited knowledge of the impact of antifungal resistance in LMICs as a consequence of limited capacity for accurate testing. Another concern is inadequate sensitivity and specificity of most tests.
Clinicians face significant challenges in treating life-threatening invasive fungal infections with a limited range of options.
In addition, healthcare workers often lack sufficient knowledge about fungal infections as well as the impact that resistance to antifungal drugs plays. This limits the ability to perform the testing needed to determine targeted treatment. The WHO calls for strengthening the global response against invasive fungal diseases and antifungal resistance, and is also developing an implementation blueprint for the FPPL.
The first report concludes, "Although some antifungal drugs are available, clinicians face significant challenges in treating life-threatening invasive fungal infections with a limited range of options. This highlights the urgent need for investment in antifungal research and development (R&D) to provide patients with better therapies and diagnostics."
